Download Glycogen synthesis

glycogen
metabolism
Glucose homeostasis
~ 20 g
~ 190 g
glucose in body fluids, mainly blood
Glycogen - liver
Glycogenolysis
after
Gluconeogenesis
~ 24 hrs starvation
Carbohydrate/glucose reserve
„Buffer role” in the maintenence of blood glucose level
Structure of glycogen
Glycogen synthesis
G-6-P - G-1-P conversion
DIPF: diisopropylfuorophosphate - inhibitor
Activated glucose
Reaction is pulled in the
forward direction by the
hydrolysis of PPi
UDP-glucose pyrophosphorylase
Primer is required
glycogenin
•
•
•
•
•
Autocatalytic activity for glycosylation
Human glycogenin gene- 1 muscle, -2 liver
5 exons
0.3% of glycogen is protein
Glycogenin content determines the cellular
glycogen content
Glycogen branching enzyme:
glycosyl (4,6) transferase,
-more soluble glycogen
-more non reducing terminal residues
increased rate of metabolism
Glycogenesis
Energy balance of glycogenesis for
one glycosyl unit
G-6-P + ATP + glycogen (n) + H2O
Glycogen (n+1) + ADP + 2Pi
Glycogen degradation
Phosphorolysis = cleavage of a bond by Pi
Energetically advantageous – released sugar is
phosphorylated
Glycogen phosphorylase
Debranching enzyme
Single
polypeptide chain
Glycogenosis = glycogen storage
disease
• Targets: liver (blood glucose homeostasis
– hypoglycaemia, hepatomegaly)
muscle (ATP production, muscle
contraction convulsions, weakness, unable
for muscle work)
Glucose-6 phosphatase enzyme system in the ER membrane
ADP increases during exercise in McArdle disease measured byNMR
Glycogen phosphorylase
Muscle
dimer or tetramer, Ser 14
phosphorylation/monomer
AMP binding site
Liver
Glucose sensor function
Regulated by allosteric interactions and
Reversible phosphorylation
Glycogen phosphorylase
Pi binding site
PLP: pyridoxal phosphate – each catalytic site contains PLP group
PLP - Schiff base
linkage at active site of
phosphorylase
active
phosphorylated
usually inactive
not phosphorylated
Equilibrium
favors
Equilibrium
favors
Allosteric binding site for nucleotides
Transition is controlled by the energy charge of the muscle cell
Glycogen phosphorylase
• Phosphorylase a is fully active regardless
of the levels of ATP/AMP, G-6-P
• Phosphorylase b is usually inactive under
physiological circumstances because of
the inhibitory effect of ATP and G-6-P
Allosteric binding site for glucose – glucose sensor function – only in liver
inactive
Under physiological conditions there is no AMP dependent regulation
Activation of phosphorylase kinase
e.g. epinephrine
δ subunit: calmodulin – calcium sensor
Glycogen synthase
• 9 sites for phosphorylation
• PKA and other protein kinases can
phosphorylate the enzyme
• Phosphorylation converts the active a form
of the enzyme to inactive b form
Reciprocal regulation in glycogen metabolism
PP1: protein phosphatase 1
• PP1 inactivates phosphorylase kinase and
phosphorylase a
• PP1 decreases glycogen breakdown
• PP1 converts glycogen synthase b to
much more active a form
• PP1 accelerates glycogen synthesis
PP1: protein phosphatase 1
Rgl: glycogen binding subunit
PP1 is active, when associated
with glycogen
Rgl can be phosphorylated by PKA
- causes dissociation from PP1 - inactive
Rgl can be phosphorylated by PKA
- causes dissociation from PP1 - inactive
Rgl can be phosphorylated by insulin sensitive protein kinase
- causes association to PP1 - active
Blood glucose regulates liver glycogen metabolism
Only in liver
Muscle phosphorylase is unaffected by glucose
Signal amplification
Regulation of blood glucose level.
Hyperglycaemia -1
• Liver
increased glucose uptake – GLUT2
Glucokinase – „extra glucose”
Increased glycogenesis – insulin; PP1 –
glycogen synthase
Decreased glycogenolysis – glucose sensor
function – glycogen phosphorylase
PDH active – increased fatty acid synthesis
Regulation of blood glucose level.
Hyperglycaemia -2
• Peripheral tissues
pancreas
increased glucose uptake – GLUT2
Glucokinase – insulin secretion
muscle, adipocytes
GLUT4 increased number in membranes
Increased glycogenesis
Decreased glycogenolysis
increased glycolysis – PFK1
Regulation of blood glucose level.
Hyperglycaemia -3
Long term effects
Decreased amount of PEPCK – decrease in
gluconeogenesis
Regulation of blood glucose level.
Hypoglycaemia
• liver
Increased gluconeogenesis
Increased glycolysis
Regulation of blood glucose level.
Hypoglycaemia
• newborns
Limited ketone body synthesis
Brain/body rate – Increased glucose
demand
PEPCK is not induced, gluconeogenesis is
not enough
Glycogen storage is limited
Glucokinase, G-6-P-ase are not induced